Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility.

Authors:
Jesús Lascorz, Asta Försti, Bowang Chen, Stephan Buch, Verena Steinke, Nils Rahner, Elke Holinski-Feder, Monika Morak, Hans K Schackert, Heike Görgens, Karsten Schulmann, Timm Goecke, Matthias Kloor, Cristoph Engel, Reinhard Büttner, Nelli Kunkel, Marianne Weires, Michael Hoffmeister, Barbara Pardini, Alessio Naccarati, Ludmila Vodickova, Jan Novotny, Stefan Schreiber, Michael Krawczak, Clemens D Bröring, Henry Völzke, Clemens Schafmayer, Pavel Vodicka, Jenny Chang-Claude, Hermann Brenner, Barbara Burwinkel, Peter Propping, Jochen Hampe, Kari Hemminki
Year of publication:
2010
Volume:
31
Issue:
9
Issn:
0143-3334
Journal title abbreviated:
CARCINOGENESIS
Journal title long:
Carcinogenesis
Impact factor:
4.874
Abstract:
Genetic susceptibility accounts for approximately 35% of all colorectal cancer (CRC). Ten common low-risk variants contributing to CRC risk have been identified through genome-wide association studies (GWASs). In our GWAS, 610 664 genotyped single-nucleotide polymorphisms (SNPs) passed the quality control filtering in 371 German familial CRC patients and 1263 controls, and replication studies were conducted in four additional case-control sets (4915 cases and 5607 controls). Known risk loci at 8q24.21 and 11q23 were confirmed, and a previously unreported association, rs12701937, located between the genes GLI3 (GLI family zinc finger 3) and INHBA (inhibin, beta A) [P = 1.1 x 10(-3), odds ratio (OR) 1.14, 95% confidence interval (CI) 1.05-1.23, dominant model in the combined cohort], was identified. The association was stronger in familial cases compared with unselected cases (P = 2.0 x 10(-4), OR 1.36, 95% CI 1.16-1.60, dominant model). Two other unreported SNPs, rs6038071, 40 kb upstream of CSNK2A1 (casein kinase 2, alpha 1 polypeptide) and an intronic marker in MYO3A (myosin IIIA), rs11014993, associated with CRC only in the familial CRC cases (P = 2.5 x 10(-3), recessive model, and P = 2.7 x 10(-4), dominant model). Three software tools successfully pointed to the overrepresentation of genes related to the mitogen-activated protein kinase (MAPK) signalling pathways among the 1340 most strongly associated markers from the GWAS (allelic P value < 10(-3)). The risk of CRC increased significantly with an increasing number of risk alleles in seven genes involved in MAPK signalling events (P(trend) = 2.2 x 10(-16), OR(per allele) = 1.34, 95% CI 1.11-1.61).